1. Field of the Invention
This invention relates to novel derivatives of acronycine and to the stabilization of such derivatives by use of suitable complexing agents. These novel derivatives, stable formulations thereof and pharmaceutical compositions comprised of same exhibit broad spectrum antitumor activity and are well suited for intravenous injection.
2. Description of the Prior Art
Svoboda et al, reported at J. Pharm. Sci., 55, pp. 758 - 768 (1966), which is hereby expressly incorporated by reference herein and is relied upon, found that the alkaloid acronycine, an acridone compound isolated from an Australian plant (Acronychia Baueri Schott), exhibits a broad antitumor activity. Tested as an ##SPC2##
Aqueous suspension, acronycine produced significant reductions in the size of a number of tumors. In the Svoboda laboratory, acronycine has been shown to be a potent antitumor agent against a multiplicity of mouse neoplasms, significant activity having been demonstrated against 12 of 17 tumors tested with a wide range of dose levels. Not only is this alkaloid broad spectrum in character, but it is also effective by various routes of administration and it has demonstrated significant activity in delayed therapy experiments. The oral and subcutaneous activities of this alkaloid are of special interest since most of the clinically proved oncolytic agents presently used are ineffective orally and elicit intolerable side effects when administered subcutaneously.
When tested against the adenocarcinoma 755, C-1498 leukemia, and the X-5563 myeloma, acronycine also displayed significant activity by both the oral and subcutaneous routes. Furthermore, there was no evidence of skin irritation or alopecia when administered subcutaneously.
However, only minimum activity was observed when this alkaloid was administered intraveneously. This was attributed to its insolubility (2-3 mg/liter), making effective clinical evaluation of this drug very difficult, sufficiently high blood levels not being attained. In fact, in several instances blockage of the circulatory system was evidenced, autopsy revealing an actual aortic block by the compound itself. One attempt at solubilizing the subject alkaloid involved coprecipitating the drug with polyvinyl-pyrrolidone (PVP); this produced only a fifteenfold increase in solubility but also an increase in antitumor activity, thus indicating that the low solubility is causing a decrease in such activity. Compare Svoboda et al, J. Pharm. Sci., 60, 333 (1971), also expressly incorporated by reference herein and relied upon.
It will thus be seen, clinical testing of acronycine having been effectively limited to the oral dosage, subcutaneous and intraperitoneal forms, that the extremely low solubility of acronycine results in marginal absorption when administered intravenously and, therefore, minimal bioavailability. Accordingly, the chemotherapeutic management of the various tumors and neoplasms being best effected by means of suitable parenteral or intravenous solution, serious need exists for a pro-drug form of acronycine which avoids the aforesaid problems of absorption and related problems of bioavailability.